The Role and Regulation of p21 in Myelopoiesis

Elevated levels of the molecular adaptor protein p21waf1/cip1 (p21) and of the IL-3 receptor alpha chain are correlated with chemoresistance and poor prognosis in acute myeloid leukemia (AML). p21 is a core regulator of many biological functions including cell cycle control, apoptosis and differentiation. Our laboratory has demonstrated a decrease in p21 expression levels during cytokine-induced granulocytic differentiation, leading us to hypothesize that p21 antagonizes granulopoiesis. The proliferative cytokine IL-3 has been shown to prevent granulocytic differentiation of murine and human myeloid progenitor cells. We also hypothesized that IL-3 inhibition of differentiation is mediated in part by p21, and tested this in murine 32Dcl3 myeloblasts that are used to model granulopoiesis. Our findings demonstrated that p21 antagonized differentiation by promoting apoptosis of cells exposed to the differentiation inducer G-CSF. We also showed that p21 prevented premature expression of primary granule proteins and contributed to maintenance of the myeloblast phenotype. Furthermore, p21 knockdown accelerated morphologic differentiation of 32Dcl3 cells stimulated to differentiate with G-CSF. We then determined how IL-3 maintains p21 expression in myeloblast cells. We showed that IL-3 stabilized p21 mRNA in myeloblasts leading to high levels of p21 protein. This effect mapped to the 3' untranslated region (UTR) of the p21 transcript. p21 transcript stabilization by IL-3 was independent of PI3-kinase and ERK pathway signaling. In vitro binding assays provided evidence that distinct sets of RNA:protein interactions occur within the proximal 303 nucleotides of the p21 3' UTR and are regulated by IL-3 and G-CSF signaling. Association of a 60-65 kDa protein with p21 riboprobes correlated with IL-3 mediated p21 mRNA stabilization, whereas binding by a 40-42 kDa protein was associated with destabilization of p21 transcripts in 32Dcl3 cells undergoing G-CSF-induced differentiation. These findings provide the first evidence for IL-3-mediated stabilization of mRNA transcripts in myeloid progenitor cells. The finding that p21 antagonized granulopoiesis is also novel. Because high levels of the IL-3 receptor and high p21 expression have separately been linked to poor outcomes in AML, IL-3 mediated p21 mRNA stabilization may contribute to differentiation blockade during AML pathogenesis

A wavelet based approach for model and parameter identification of nonlinear systems

A procedure is presented for identifying the mechanical parameters of zero-memory non-linear discrete structural systems. The procedure allows both the parameter estimation of a priori known dynamical models as well as the identi"cation of classes of suitable non-linear models based on input}output data. The method relies on a wavelet-based discretization of the non-linear governing di!erential equation of motion. Orthogonal Daubechies scaling functions are used in the analysis. The scaling functions localization properties permit the tracking of fast variations of the state of the dynamical system which may be associated with unmodeled dynamics of measurement noise. The method is based on the knowledge of measured state variables and excitations and applies to single and multi-degree-of-freedom systems under either free or forced vibrations

Coarse-graining the dynamics of coupled oscillators

We present an equation-free computational approach to the study of the coarse-grained dynamics of {\it finite} assemblies of {\it non-identical} coupled oscillators at and near full synchronization. We use coarse-grained observables which account for the (rapidly developing) correlations between phase angles and oscillator natural frequencies. Exploiting short bursts of appropriately initialized detailed simulations, we circumvent the derivation of closures for the long-term dynamics of the assembly statistics.Comment: accepted for publication in Phys. Rev. Let

Optimal Resource Allocation for Multi-user OFDMA-URLLC MEC Systems

In this paper, we study resource allocation algorithm design for multi-user orthogonal frequency division multiple access (OFDMA) ultra-reliable low latency communication (URLLC) in mobile edge computing (MEC) systems. To meet the stringent end-to-end delay and reliability requirements of URLLC MEC systems, we propose joint uplink-downlink resource allocation and finite blocklength transmission. Furthermore, we employ a partial time overlap between the uplink and downlink frames to minimize the end-to-end delay, which introduces a new time causality constraint. The proposed resource allocation algorithm is formulated as an optimization problem for minimization of the total weighted power consumption of the network under a constraint on the number of URLLC user bits computed within the maximum allowable computation time, i.e., the end-to-end delay of a computation task. Despite the non-convexity of the formulated optimization problem, we develop a globally optimal solution using a branch-and-bound approach based on discrete monotonic optimization theory. The branch-and-bound algorithm minimizes an upper bound on the total power consumption until convergence to the globally optimal value. Furthermore, to strike a balance between computational complexity and performance, we propose two efficient suboptimal algorithms based on successive convex approximation and second-order cone techniques. Our simulation results reveal that the proposed resource allocation algorithm design facilitates URLLC in MEC systems, and yields significant power savings compared to three baseline schemes. Moreover, our simulation results show that the proposed suboptimal algorithms offer different trade-offs between performance and complexity and attain a close-to-optimal performance at comparatively low complexity.Comment: 32 pages, 9 figures, submitted for an IEEE journal. arXiv admin note: substantial text overlap with arXiv:2005.0470